Pim kinase inhibitors in combination with rna splicing modulators/inhibitors for treatment of cancers

A composition comprising a combination of therapeutically synergistic amounts of at least one a PIM kinase inhibitor that exhibits changes and/or disruption of mRNA splicing in combination with a compound that modulates and/or inhibits splicing activity of an RNA splicing factor, wherein the at least one PIM kinase inhibitor is SGI-1776 (N-[(1-methylpiperidin-4-yl)methyl]-3-[3-(trifluoromethoxy)phenyl]imidazo[1,2-b]pyridazin-6-amine), SMI-4a (5-[[3-(trifluoromethyl)phenyl]methylidene]-1,3-thiazolidine-2,4-dione), CX-6258 (E)-5-chloro-3-((5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one), LKB1 (N-[5-(4-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyridine-3-carboxamide), AZD1208 ((5E)-5-[[2-[(3R)-3-aminopiperidin-1-yl]-3-phenylphenyl]methylidene]-1,3-thiazolidine-2,4-dione), PIM-1 Inhibitor 2 (4-[3-(4-chlorophenyl)-2,1-benzoxazol-5-yl]pyrimidin-2-amine), R8-T198 wt or TCS PIM-1 (6-(5-bromo-2-hydroxyphenyl)-2-oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile), and wherein the compound that modulates and/or inhibits splicing activity of a RNA splicing factor is natural product of Pseudomonas sp. number 2663 (FR901464), natural products from Streptomyces platensis Mer-11107, pladienolide B, herboxidien, trichostatin, isoginkgetin, 2-((7methoxy-4-methylquinazolin-2-yl)amino)-5,6-dimethylpyrimidin-4(3H)-one, bovine papillomavirus type 1 (BPV-1) exonic splicing suppressor (ESS), or N-[2-(1-Piperidinyl)-5-(trifluoromethyl)phenyl]-4-pyridinecarboxamide (SRPIN340), wherein the cancer is selected from the group consisting of:

• bone cancer, gynecological cancer, breast cancer, hematological malignancy, skin cancer, liver cancer, kidney cancer, pancreatic cancer, brain cancer, lung cancer, and prostate cancer and wherein the combination has a therapeutic effect on cancerous tissue which is greater than the sum of the individual therapeutic effects of the individual compounds.